The title of this project is Treating Collagen-induced Arthritis with Fc? Receptor Activating Nanoparticles. We and others have identified and characterized a population of macrophages with potent immunorergulatory activity. The goal of the present proposal is to induce the production of regulatory macrophages (R-M?) in mice, and determine whether their induction can decrease pathology associated with collagen-induced arthritis (CIA). To induce R-M?, mice will be injected with Fc? Receptor Activating Nanoparticle (Fc?RANP). We have established a collaborative arrangement in which LeukoSight will produce and purify proprietary polypeptides that bind to Fc? receptors on macrophages. In collaboration with Dr. Christopher Jewell, at the University of Maryland, these polypeptides will be tethered to nanoparticles and tested for their ability to reprogram macrophages into R-M?. Fc?RANP with the highest reprogramming activity will then be tested in two models of CIA. In the first model, mice will be injected with Type II Collagen in CFA and then administered Fc?RANP prior to the induction of disease. A delay in the onset of disease or a decrease in severity will be measured over the next several weeks (Aim 1). In the second model, clinically apparent CIA will be induced in mice by the injection of C-II in CFA and then after the mice show symptoms of established disease, they will be injected with Fc?RANP. Over the next two weeks the resolution of symptoms and a decrease in pathology will be examined and quantified (Aim 2). The decrease in pathology will be correlated with the appearance of R-M? in the joint synovium. LeukoSight, Inc has invested substantial time and effort into identifying recombinant polypeptides that bind avidly to macrophage Fc?R and they have developed a reliable assay to measure regulatory macrophage reprogramming. The university research laboratories of Drs. Mosser and Jewell have proficiency in a variety of autoimmune disease models, including CIA. The University has provided IACUC approval to perform these studies. The goal of these studies is to demonstrate the feasibility of using nanoparticle-based macrophage reprogramming as a therapeutic strategy to treat autoimmune diseases.